N-(imidazolidin-2-ylidene)quinoline derivatives as modulators of alpha 2 adrenergic receptors

ABSTRACT

The present invention relates to novel N-(imidazolidin-2-ylidene)quinoline derivatives, processes for preparing them, pharmaceutical compositions containing them and their use as pharmaceuticals.

RELATED APPLICATION

This application claims the benefit of U.S. Provisional Application Ser.No. 61/511,298, filed Jul. 25, 2011, the disclosure of which is herebyincorporated in its entirety herein by reference.

FIELD OF THE INVENTION

The present invention relates to novelN-(imidazolidin-2-ylidene)quinoline derivatives, as alpha 2 adrenergicmodulators. Alpha 2 adrenergic receptors have been characterized bymolecular and pharmacological methods which include alpha 1A, alpha1B,alpha 2A, alpha 2B and alpha 2C. Activation of these alpha receptorsevokes physiological responses. Adrenergic modulators described in thisinvention activate alpha 2 receptors and have useful therapeuticactions.

BACKGROUND OF THE INVENTION

Human adrenergic receptors are integral membrane proteins which havebeen classified into two broad classes, the alpha and the betaadrenergic receptors. Both types mediate the action of the peripheralsympathetic nervous system upon binding of catecholamines,norepinephrine and epinephrine. Norepinephrine is produced by adrenergicnerve endings, while epinephrine is produced by the adrenal medulla. Thebinding affinity of adrenergic receptors for these compounds forms onebasis of the classification: alpha receptors tend to bind norepinephrinemore strongly than epinephrine and much more strongly than the syntheticcompound isoproterenol. The preferred binding affinity of these hormonesis reversed for the beta receptors. In many tissues, the functionalresponses, such as smooth muscle contraction, induced by alpha receptoractivation are opposed to responses induced by beta receptor binding.

Subsequently, the functional distinction between alpha and betareceptors was further highlighted and refined by the pharmacologicalcharacterization of these receptors from various animal and tissuesources. Functional differences between α₁ and α₂ receptors have beenrecognized, and compounds which exhibit selective binding between thesetwo subtypes have been developed.

U.S. Pat. No. 6,723,741 discloses benzimidazoles and benzothiazoles asalpha 2 adrenergic receptor agonists.

SUMMARY OF THE INVENTION

The present invention relates to novelN-(imidazolidin-2-ylidene)quinoline derivatives, as alpha 2 adrenergicmodulators. These novel compounds will be useful for the treatment ofmammals, including humans, with a range of conditions and diseases thatare alleviated by alpha 2A, 2B, 2C activation, including but not limitedto treating glaucoma, elevated intraocular pressure, ischemicneuropathies, optic neuropathy, pain, visceral pain, corneal pain,headache pain, migraine, cancer pain, back pain, irritable bowelsyndrome pain, muscle pain and pain associated with diabetic neuropathy,other retinal degenerative conditions, stroke, cognitive deficits,neuropsychiatric conditions, drug dependence and addiction, withdrawalsymptoms, obsessive-compulsive disorders, obesity, insulin resistance,stress-related conditions, diarrhea, diuresis, nasal congestion,spasticity, attention deficit disorder, psychoses, anxiety, depression,autoimmune disease, Crohn's disease, gastritis, Alzheimer's, Parkinson'sALS, neurodegenerative diseases, retinal neuroprotection, skinconditions, skin diseases, rosacea, sunburn, psoriasis, acne rosacea,menopause-associated hot flashes, hot flashes resulting fromorchiectomyatopic dermatitis, photoaging, seborrheic dermatitis, acne,allergic dermatitis, redness of the skin, treatment of redness and itchfrom insect bites, flushing and redness associated with hot flashes,erythema associated with hot flashes, telangiectasia (dilations ofpreviously existing small blood vessels) of the face, rhinophymia(hypertrophy of the nose with follicular dilation), red bulbous nose,acne-like skin eruptions (may ooze or crust), burning or stingingsensation, irritated and bloodshot and watery eyes, erythema of theskin, cutenous hyperactivity with dilation of blood vessels of the skin,Lyell's syndrome, Stevens-Johnson syndrome, erythema multiforme minor,erythema multiforme major and or other inflammatory skin diseases, agerelated macular degeneration, wet macular degeneration, dry maculardegeneration, geographic atrophy, diabetic retinopathy, diabetic macularedema, tumors, wound healing, inflammation and retinal vein occlusion,enhancing vision in patients with vision loss from conditions includingglaucoma, retinitis pigmentosa and neuritis secondary to multiplesclerosis.

In one aspect, the invention therefore provides a compound of Formula I,its enantiomers, diastereoisomers, hydrates, solvates, crystal forms andtautomers or a pharmaceutically acceptable salt thereof

wherein:

R¹ is hydrogen, substituted or unsubstituted C₁₋₈ alkyl or halogen;

Y is CH or N;

X is CH or N; and

compound N-(imidazolidin-2-ylidene)quinolin-4-amine;

except compound N-(4,5-dihydro-1H-imidazol-2-yl)-3-quinolinamine.

In another aspect, the invention provides a compound of Formula Iwherein:

R¹ is hydrogen, methyl, bromine or chlorine;

Y is CH or N; and

X is CH or N;

except compound N-(4,5-dihydro-1H-imidazol-2-yl)-3-quinolinamine.

In another aspect, the invention provides a compound of Formula Iwherein:

R¹ is methyl, bromine or chlorine;

Y is CH or N; and

X is CH or N.

In another aspect, the invention provides a compound of Formula Iwherein:

R¹ is methyl, bromine or chlorine;

Y is CH or N; and

X is CH or N.

In another aspect, the invention provides a compound of Formula Iwherein:

R¹ is methyl;

Y is CH or N; and

X is CH or N.

In another aspect, the invention provides a compound of Formula Iwherein:

R¹ is bromine;

Y is CH or N; and

X is CH or N.

In another aspect, the invention provides a compound of Formula Iwherein:

R¹ is chlorine;

Y is CH or N; and

X is CH or N.

In another aspect, the invention provides a compound of Formula Iwherein:

R¹ is chlorine;

Y is CH or N; and

X is CH.

In another aspect, the invention provides a compound of Formula Iwherein:

R¹ is chlorine;

Y is CH; and

X is CH or N.

The term “alkyl” as used herein, is defined as including a saturatedmonovalent hydrocarbon moiety having straight or branched moieties orcombinations thereof and containing 1-8 carbon atoms, preferably 1-6carbon atoms and more preferably 1-4 carbon atoms. Alkyl moieties canoptionally be substituted by amino groups, halogens or one methylene(—CH₂—) can be replaced by carbonyl, NH, carboxyl or by oxygen.

The term “H” as used herein refers to a hydrogen atom.

The term “O” as used herein refers to an oxygen atom.

The term “N” as used herein refers to a nitrogen atom.

The term “amino” as used herein refers to a group of formula —NH₂.

The term “halogen”, as used herein refers to an atom of chlorine,bromine, iodine or fluorine.

The term “carbonyl” as used herein refers to a group of formula —C═O.

The term “carboxyl”, as used herein refers to a group of formula—C(O)O—.

Compounds of the invention are:

-   N-(imidazolidin-2-ylidene)quinolin-4-amine;-   N-(imidazolidin-2-ylidene)-4-methylquinolin-3-amine;-   4-Chloro-N-(imidazolidin-2-ylidene)quinolin-3-amine;-   4-Bromo-N-(imidazolidin-2-ylidene)quinolin-3-amine;-   N-(imidazolidin-2-ylidene)pyrido[2,3-b]pyrazin-7-amine;-   N-(imidazolidin-2-ylidene)-8-methylpyrido[2,3-b]pyrazin-7-amine;-   4-Chloro-N-(imidazolidin-2-ylidene)-1,5-naphthyridin-3-amine.

Some compounds of Formula I and some of their intermediates have atleast one stereogenic center in their structure. This stereogenic centermay be present in an R or S configuration, said R and S notation is usedin correspondence with the rules described in Pure Appli. Chem. (1976),45, 11-13.

As used herein, “tautomer” refers to the migration of protons betweenadjacent single and double bonds. The tautomerization process isreversible. Compounds described herein can undergo any possibletautomerization that is within the physical characteristics of thecompound:

The term “pharmaceutically acceptable salts” refers to salts orcomplexes that retain the desired biological activity of the aboveidentified compounds and exhibit minimal or no undesired toxicologicaleffects. The “pharmaceutically acceptable salts” according to theinvention include therapeutically active, non-toxic base or acid saltforms, which the compounds of Formula I are able to form.

The acid addition salt form of a compound of Formula I that occurs inits free form as a base can be obtained by treating the free base withan appropriate acid such as an inorganic acid, for example hydrochloricacid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid andthe like; or an organic acid for example acetic acid, hydroxyaceticacid, propanoic acid, lactic acid, pyruvic acid, malonic acid, fumaricacid, maleic acid, oxalic acid, tartaric acid, succinic acid, malicacid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, citric,methylsulfonic acid, ethanesulfonic acid, benzenesulfonic acid, formicand the like (Handbook of Pharmaceutical Salts, P. Heinrich Stahal &Camille G. Wermuth (Eds), Verlag Helvetica Chemica Acta-Zürich, 2002,329-345).

The invention also provides a pharmaceutical composition comprising atherapeutically effective amount of the compounds described above andpharmaceutically acceptable carriers, diluents, excipients. In thepresent invention a “therapeutically effective amount” is any amount ofa compound which, when administered to a subject suffering from adisease against which the compounds are effective, causes reduction,remission, or regression of the disease.

The pharmaceutical carrier can be a liquid and the pharmaceuticalcomposition can be in the form of a solution. The pharmaceuticallyacceptable carrier can be a solid and the composition can be in the formof a powder, capsule or tablet. In a further embodiment, thepharmaceutical carrier can be a gel and the composition can be in theform of a suppository or cream. In a further embodiment the compound maybe formulated as a part of a pharmaceutically acceptable transdermalpatch.

A solid carrier can include one or more substances which may also act asflavoring agents, lubricants, solubilizers, suspending agents, fillers,glidants, compression aids, binders or tablet-disintegrating agents; itcan also be an encapsulating material. In powders, the carrier is afinely divided solid which is in admixture with the finely dividedactive ingredient. In tablets, the active ingredient is mixed with acarrier having the necessary compression properties in suitableproportions and compacted in the shape and siz desired. The powders andtablets preferably contain up to 99% of the active ingredient. Suitablesolid carriers include, for example, calcium phosphate, magnesiumstearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose,polyvinylpyrrolidine, low melting waxes and ion exchange resins. Liquidcarriers are used in preparing solutions, suspensions, emulsions,syrups, elixirs and pressurized compositions. The active ingredient canbe dissolved or suspended in a pharmaceutically acceptable liquidcarrier such as water, an organic solvent, a mixture of both orpharmaceutically acceptable oils or fats. The liquid carrier can containother suitable pharmaceutical additives such as solubilizers,emulsifiers, buffers, preservatives, sweeteners, flavoring agents,suspending agents, thickening agents, colors, viscosity regulators,stabilizers or osmo-regulators.

Suitable examples of liquid carriers for oral and parenteraladministration include water (partially containing additives as above,e.g. cellulose derivatives, preferably sodium carboxymethyl cellulosesolution), alcohols (including monohydric alcohols and polyhydricalcohols, e.g. glycols) and their derivatives, and oils (e.g.fractionated coconut oil and arachis oil). For parenteraladministration, the carrier can also be an oily ester such as ethyloleate and isopropyl myristate. Sterile liquid carriers are useful insterile liquid form compositions for parenteral administration. Theliquid carrier for pressurized compositions can be halogenatedhydrocarbon or other pharmaceutically acceptable propellent.

Compounds of Formula I and their salts can be in the form of a solvate,which is included within the scope of the present invention. Suchsolvates include for example hydrates, alcoholates and the like.

With respect to the present invention reference to a compound orcompounds, is intended to encompass that compound in each of itspossible isomeric forms and mixtures thereof unless the particularisomeric form is referred to specifically.

Compounds according to the present invention may exist in differentpolymorphic forms. Although not explicitly indicated in the aboveformula, such forms are intended to be included within the scope of thepresent invention.

The actual amount of the compound to be administered in any given casewill be determined by a physician taking into account the relevantcircumstances, such as the severity of the condition, the age and weightof the patient, the patient's general physical condition, the cause ofthe condition, and the route of administration.

The patient will be administered the compound orally in any acceptableform, such as a tablet, liquid, capsule, powder and the like, or otherroutes may be desirable or necessary. Such other routes may include,without exception, transdermal, parenteral, subcutaneous, intranasal,via an implant stent, intrathecal, intravitreal, topical to the eye,back of the eye, front of the eye, intramuscular, intravenous, andintrarectal modes of delivery. Additionally, the formulations may bedesigned to delay release of the active compound over a given period oftime, or to carefully control the amount of drug released at a giventime during the course of therapy.

In another aspect the invention relates to a method for treating acondition alleviated by alpha 2A, 2B, 2C activation, in a patient inneed thereof which comprises administering a pharmaceutical compositioncomprising a therapeutically effective amount of compound of Formula Ior a pharmaceutically acceptable salt thereof.

In another embodiment of the invention, there are providedpharmaceutical compositions including at least one compound of theinvention in a pharmaceutically acceptable carrier thereof. The phrase“pharmaceutically acceptable” means the carrier, diluent or excipientmust be compatible with the other ingredients of the formulation and notdeleterious to the recipient thereof.

In another embodiment of the invention, there is provided an article ofmanufacture comprising packaging material and a pharmaceutical agentcontained within said packaging material, wherein the pharmaceuticalagent is therapeutically effective and wherein the packaging materialcomprises a label which indicates the pharmaceutical agent can be usedfor treating a disorder associated with the alpha 2 receptors andwherein said pharmaceutical agent comprises an effective amount of atleast one compound of Formula I.

Since individual subjects may present a wide variation in severity ofsymptoms and each drug has its unique therapeutic characteristics, theprecise mode of administration and dosage employed for each subject isleft to the discretion of the practitioner.

The synthetic scheme set forth below, illustrates how compoundsaccording to the invention can be made. Those skilled in the art will beable to routinely modify and/or adapt the following scheme to synthesizeany compounds of the invention covered by Formula I.

The synthesis of compounds of Formula I was started with thepyridine-3-amine derivative, which treated with thiophosgene (CSCl₂) inthe presence of triethylamine (Et₃N) in tetrahydrofuran gave theisothiocyanate key intermediate. The isothiocyanate was then reactedwith ethane-1,2-diamine followed by mercury oxide treatment in methanoland afforded the desired compound of Formula I.

DETAILED DESCRIPTION OF THE INVENTION

It is to be understood that both the foregoing general description andthe following detailed description are exemplary and explanatory onlyand are not restrictive of the invention claimed. As used herein, theuse of the singular includes the plural unless specifically statedotherwise.

It will be readily apparent to those skilled in the art that some of thecompounds of the invention may contain one or more asymmetric centers,such that the compounds may exist in enantiomeric as well as indiastereomeric forms. Unless it is specifically noted otherwise, thescope of the present invention includes all enantiomers, diastereomersand racemic mixtures. Some of the compounds of the invention may formsalts with pharmaceutically acceptable acids or bases, and suchpharmaceutically acceptable salts of the compounds described herein arealso within the scope of the invention.

The present invention includes all pharmaceutically acceptableisotopically enriched compounds. Any compound of the invention maycontain one or more isotopic atoms enriched or different than thenatural ratio such as deuterium ²H (or D) in place of protium ¹H (or H)or use of ¹³C enriched material in place of ¹²C and the like. Similarsubstitutions can be employed for N, O and S. The use of isotopes mayassist in analytical as well as therapeutic aspects of the invention.For example, use of deuterium may increase the in vivo half-life byaltering the metabolism (rate) of the compounds of the invention. Thesecompounds can be prepared in accord with the preparations described byuse of isotopically enriched reagents.

The following examples are for illustrative purposes only and are notintended, nor should they be construed as limiting the invention in anymanner. Those skilled in the art will appreciate that variations andmodifications of the following examples can be made without exceedingthe spirit or scope of the invention.

The IUPAC names of the compounds mentioned in the examples weregenerated with ACD version 12.5.

Unless specified otherwise in the examples, characterization of thecompounds is performed according to the following methods:

NMR spectra are recorded on 300 MHz Varian and acquired at roomtemperature. Chemical shifts are given in ppm referenced either tointernal TMS or to the residual solvent signal.

All the reagents, solvents, catalysts for which the synthesis is notdescribed are purchased from chemical vendors such as Sigma Aldrich,Fluka, Lancaster, however some known reaction intermediates, for whichthe CAS registry number is mentioned, were prepared in-house followingknown procedures.

Usually the compounds of the invention were purified by flash columnchromatography.

The following abbreviations are used in the examples:

DCM dichloromethane

EtOH ethanol

MeOH methanol

NH₃ ammonia

EtOAc ethylacetate

TEA triethylamine

CSCl₂ thiophosgene

THF tetrahydrofuran

Example 1 Intermediate 1 1-(2-Aminoethyl)-3-(quinolin-4-yl)thiourea

To a solution of ethane-1,2-diamine (CAS 107-15-3) (704 mg, 4.5 eq) inbenzene (10 mL) was added a solution of 4-isothiocyanato-quinoline (CAS868163-42-2) (480 mg, 2.61 mmol) in benzene (5 mL). The resultingmixture was stirred at room temperature for 16 h. The productprecipitated as a pale yellow solid, which was filtered to collect thesolid washed with ether and gave Intermediate 1.

Example 2 Intermediate 2 4-Chloro-3-isothiocyanato-1,5-naphthyridine

To a solution of 4-chloro-1,5-naphthyridin-3-amine (CAS 930276-73-6)(550 g, 3.07 mmol) in THF (10 mL) was added TEA (0.95 mL, 6.76 mmol)followed by CSCl₂ (0.26 mL, 3.4 mmol) at 0° C. The mixture was stirredat room temperature for 2 h. Celite (2 g) was added to the reactionmixture, then concentrated and purified by silica gel columnchromatography using hexane:EtOAc (7:3) and gave Intermediate 2 (360mg).

Example 3 Intermediate 31-(2-Aminoethyl)-3-(4-chloro-1,5-naphthyridin-3-yl)thiourea

To a solution of ethane-1,2-diamine (CAS 107-15-3) (0.54 mL, 8.12 mmol)in benzene (10 mL) was added a solution of Intermediate 2 (360 mg) inbenzene (5 mL). The resulting mixture was stirred at room temperaturefor 16 h. Benzene and excess of ethane-1,2-diamine were decanted. Theproduct was washed with ethyl-ether and yielded Intermediate 3.

Example 4 Compound 1 N-(imidazolidin-2-ylidene)quinolin-4-amine

Intermediate 1 was taken in EtOH (15 mL) with mercury oxide (618 mg) andheated at reflux temperature for 4 h. The mixture was cooled to roomtemperature and filtered through celite. Silica gel was added to thefiltrate and concentrated and purified by chromatography on silica gelwith 5% NH₃-MeOH:DCM and gave (68 mg) Compound 1 as a white solid.

¹H NMR (Methanol-d₆) δ: 8.54 (d, J=5.0 Hz, 1H), 8.23 (d, J=7.9 Hz, 1H),7.88 (d, J=8.5 Hz, 1H), 7.61-7.72 (m, 1H), 7.41-7.53 (m, 1H), 7.05 (d,J=5.3 Hz, 1H), 3.56 (s, 4H).

Example 5 Compound 24-Chloro-N-(imidazolidin-2-ylidene)-1,5-naphthyridin-3-amine

Intermediate 3 was taken in EtOH (15 mL) with mercury oxide (422 mg) andheated at reflux temperature for 2 h. The mixture was cooled to roomtemperature filtered through celite. Silica gel was added to thefiltrate concentrated and purified by silica gel chromatography using 5%NH₃-MeOH:DCM and gave (120 mg) Compound 2.

¹H NMR (Methanol-d₄) δ: 8.90 (dd, J=4.1, 1.5 Hz, 5H), 8.68 (s, 1H), 8.36(dd, J=8.2, 1.5 Hz, 1H), 7.66 (dd, J=8.5, 4.4 Hz, 1H), 3.56 (s, 4H).

Compounds 3, 4, 5, 6 and 7 were prepared in a similar manner to themethod described in Example 5 for Compound 2 starting with thecorresponding starting material. The results are tabulated below inTable 1.

TABLE 1 Com- ¹ NMR (Solvent; pound IUPAC name δ ppm) 3

¹H NMR (Methanol- d₄) δ: 8.46 (s, 1H), 8.02-8.09 (m, 1H), 7.89-7.98 (m,1H), 7.51-7.67 (m, 2H), 3.52 (s, 4H), 2.56 (s, 3H) 4

¹H NMR (Methanol- d₄) δ: 8.55 (s, 1H), 8.14-8.22 (m, 1H), 7.92-8.00 (m,1H), 7.57-7.68 (m, 2H), 3.52 (s, 4H) 5

¹H NMR (Methanol- d₄) δ: 8.49 (s, 1H), 8.16-8.23 (m, 1H), 7.92-7.99 (m,1H), 7.60-7.68 (m, 2H), 3.52 (s, 4H) 6

¹H NMR (Methanol- d₄) δ: 8.76-8.85 (m, 3H), 7.88 (d, J = 2.6 Hz, 1H),3.59 (s, 4H) 7

¹H NMR (Methanol- d₄) δ: 8.90 (d, J = 1.8 Hz, 4H), 8.85 (d, J = 1.8 Hz,1H), 8.73 (s, 1H), 3.53 (s, 4H), 2.64 (s, 3H)

The following assay was used to demonstrate the potency and selectivityof the compounds according to the invention.

Example 6 RSAT Compound Screening

Novel compounds were synthesized and tested for alpha adrenergicactivity using the Receptor Selection and Amplification Technology(RSAT) assay (Messier et. al., 1995, Pharmacol. Toxicol. 76, pp.308-311). Cells expressing each of the alpha2 adrenergic receptors alonewere incubated with the various compounds and a receptor-mediated growthresponse was measured. The compound's activity was expressed as itsrelative efficacy compared to a standard full agonist (see Table 2). Thecompounds of this invention activate alpha 2 receptors.

TABLE 2 Biological Data: Intrinsic Activity EC₅₀ nM (efficacy) Compoundnumber IUPAC name Alpha 2C 1 N-(imidazolidin-2-ylidene)quinolin-4-  17.4(0.95) amine 2 4-Chloro-N-(imidazolidin-2-ylidene)-1,5-  21 (0.95)naphthyridin-3-amine 3 N-(imidazolidin-2-ylidene)-4- 1653 (0.21)methylquinolin-3-amine 4 4-Chloro-N-(imidazolidin-2-  368 (0.66)ylidene)quinolin-3-amine 5 4-Bromo-N-(imidazolidin-2- 1529 (0.17)ylidene)quinolin-3-amine 6 N-(imidazolidin-2-ylidene)pyrido[2,3- 4581(0.44) b]pyrazin-7-amine 7 N-(imidazolidin-2-ylidene)-8-  311 (0.93)methylpyrido[2,3-b]pyrazin-7-amine

What is claimed is:
 1. A compound of Formula I, an enantiomer, adiastereoisomer, a tautomer or a pharmaceutically acceptable saltthereof,

wherein: R¹ is hydrogen, substituted or unsubstituted C₁₋₈ alkyl orhalogen; Y is CH or N; X is CH or N; except compoundN-(4,5-dihydro-1H-imidazol-2-yl)-3-quinolinamine.
 2. A compoundaccording to claim 1 wherein: R¹ is hydrogen, methyl, bromine orchlorine; Y is CH or N; X is CH or N.
 3. A compound according to claim 1wherein: R¹ is methyl, bromine or chlorine; Y is CH or N; and X is CH orN.
 4. A compound according to claim 1 wherein: R¹ is methyl; Y is CH orN; and X is CH or N.
 5. A compound according to claim 1 wherein: R¹ isbromine; Y is CH or N; and X is CH or N.
 6. A compound according toclaim 1 wherein: R^(z1) is chlorine; Y is CH or N; and X is CH or N. 7.A compound according to claim 1 wherein: R¹ is chlorine; Y is CH or N;and X is CH.
 8. A compound according to claim 1 wherein: R¹ is chlorine;Y is CH; and X is CH or N.
 9. A compound according to claim 1 selectedfrom: N-(imidazolidin-2-ylidene)-4-methylquinolin-3-amine;4-Chloro-N-(imidazolidin-2-ylidene)quinolin-3-amine;4-Bromo-N-(imidazolidin-2-ylidene)quinolin-3-amine;N-(imidazolidin-2-ylidene)pyrido[2,3-b]pyrazin-7-amine;N-(imidazolidin-2-ylidene)-8-methylpyrido[2,3-b]pyrazin-7-amine; and4-Chloro-N-(imidazolidin-2-ylidene)-1,5-naphthyridin-3-amine.
 10. Apharmaceutical composition comprising as active ingredient atherapeutically effective amount of a compound according to claim 1 anda pharmaceutically acceptable adjuvant, diluents or carrier.
 11. Apharmaceutical composition according to claim 10 wherein the compound isselected from: N-(imidazolidin-2-ylidene)-4-methylquinolin-3-amine;4-Chloro-N-(imidazolidin-2-ylidene)quinolin-3-amine;4-Bromo-N-(imidazolidin-2-ylidene)quinolin-3-amine;N-(imidazolidin-2-ylidene)pyrido[2,3-b]pyrazin-7-amine;N-(imidazolidin-2-ylidene)-8-methylpyrido[2,3-b]pyrazin-7-amine; and4-Chloro-N-(imidazolidin-2-ylidene)-1,5-naphthyridin-3-amine.
 12. Acompound which is N-(imidazolidin-2-ylidene)quinolin-4-amine.